Abstract
Matrix metalloproteinases (MMPs) are extracellular matrix degradation factors, promoting cancer progression. Hence, they could provide an enzyme-assisted delivery of doxorubicin (DOX) in cancer treatment. In the current study, the intercalation process of DOX and tetrapeptide–DOX, the product of the MMPs’ cleavage of carrier-linked DOX, into dsDNA was investigated using stationary and time-resolved fluorescence spectroscopy, UV-Vis spectrophotometry and isothermal titration calorimetry (ITC). The molecular dynamics (MD) simulations on the same tetrapeptide–DOX…DNA and DOX…DNA systems were also performed. The undertaken studies indicate that DOX and tetrapeptide–DOX can effectively bond with dsDNA through the intercalation mode; however, tetrapeptide–DOX forms less stable complexes than free DOX. Moreover, the obtained results demonstrate that the differences in DNA affinity of both forms of DOX can be attributed to different intercalation modes. Tetrapeptide–DOX shows a preference to intercalate into DNA through the major groove, whereas DOX does it through the minor one. In summary, we can conclude that the tetrapeptide–DOX intercalation to DNA is significant and that even the lack of non-specific proteases releasing DOX from the tetrapeptide conjugate, the presence of which is suggested by the literature for the efficient release of DOX, should not prevent the cytostatic action of the anthracycline.
Highlights
Cancer—the second leading cause of death worldwide—can be treated by several modalities, of which chemotherapy represents 36% of the treatment options [1,2]
We present the synthesis of a tetrapeptide–DOX conjugate (Leu–Ala–Gly–Gly–DOX, i.e., 4-pep–DOX), as a potential result of Matrix metalloproteinases (MMPs)’ action on the substrate peptide sequence (Figure 1)
The experimental and theoretical studies demonstrated that the presence of tetrapeptide does not affect the overall tendency of DOX to intercalate into dsDNA, but rather changes its binding mode
Summary
Cancer—the second leading cause of death worldwide—can be treated by several modalities, of which chemotherapy represents 36% of the treatment options [1,2]. One of the strategies to increase therapeutic efficiency, with high binding specificity and reduced toxic effects of a drug, is to conjugate it with polymers, lipid nanoparticles, or antibody–drug conjugates [14,15,16] Such an approach can lead to a system characterized by enhanced solubility, permeability, and retention in body plasma that triggers drug release in cancer cells [17]. There are a series of substrate peptide sequences degradable in the presence of MMPs, e.g., Gly–Pro–Leu–Gly–Ile–Ala–Gly–Gln, Pro–Val–Gly–Leu–Ile–Gly, or Pro–Leu–Gly–Val–Arg, where cleavage occurs between leucine (Leu) and glycine (Gly) [25,26,27] Using this approach, new polymer–drug conjugates with a selective peptide sequence between the carrier (polymer) and the cargo (drug) have been designed [28].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
